A number of review articles describe the characterization and therapeutic relevance of the prostanoid receptors as well as the most commonly used selective agonists and antagonists; Eicosanoids: From Biotechnology to therapeutic Applications, Folco, Samuelson, Maclouf and Velo eds, Plenum Press, New York, 1996, chap. 14, 137-154; “Molecular aspects of the structures and functions of the prostaglandin E receptors”, Journal of Lipid Mediators and Cell Signalling, 1996, 14, 83-87; “Function of prostanoid receptors: studies on knockout mice”, Prostaglandins & other Lipid Mediators, 2002, 68-69, 557-573 and “Prostanoid receptor antagonists: development strategies and therapeutic applications”, British Journal of Pharmacology (2009), 158, 104-145. Prostaglandin E2 (PGE2) is a member of the prostanoid family with a variety of physiological effects, including mucosal protection, induction of gastris acid secretion in stomach, generation of fever, hyperalgesia, inflammation and immunity. These actions of PGE2 are mediated by four G-protein-coupled PGE2 receptors, EP1, EP2, EP3 and EP4.
The EP4 receptor is a 7-transmembrane receptor whose activation is normally associated with elevation of intracellular cyclic adenosine monophosphate (cAMP) levels. PGE2-activated EP4 receptor signalling may be involved in various pathologic states, such as pain, inflammation, cancer, dermatitis, bone disease and immune system disfunction.
In The Journal of Immunology (2008, 181, 5082-5088) studies suggest that PGE2 inhibits proteoglycan synthesis and stimulates matrix degradation in osteoarthritic chondrocytes via the EP4 receptor. Targeting EP4, rather than cyclooxygenase 2, could represent a future strategy for osteoarthritis disease modification.
In European Journal of Pharmacology (2008, 580, 116-121) studies suggest that that a pharmacological blockade of the prostanoid EP4 receptor may represent a new therapeutic strategy in signs and symptomatic relief of osteoarthritis and/or rheumatoid arthritis.
Certain nicotinamide compounds are generally disclosed in US20022111495A, said compounds being described as inhibitors of phosphodiesterases 4 isoenzymes. Patent application publications WO2005021508, WO2005105732, WO2005105733, WO2007121578 and WO2009139373 disclose compounds as being useful in the treatment of prostaglandin mediated disease.